Carbohydrate structures can be tumour-specific or tumour-associated antigens and are thus the focus of many antibody-generating immunization strategies. However, generating anti-carbohydrate specific antibodies is a challenging task as they may lack specificity, affinity or are only of the IgM class (Christensen et al., 2009). Moreover, generating humanised anti-carbohydrate antibodies that have the capacity to kill cancer cells is a challenging task, a fact that is reflected in the rare number of reports on such antibodies. There is only one example of an anti-glycolipid antibody that has been successfully humanised; the antibody recognises the ganglioside GM2 and kills human tumour cells in vitro and in vivo (U.S. Pat. Nos. 6,423,511 and 6,872,392). Although not humanised there are two other examples of carbohydrate-binding antibodies that have been engineered for human administration. Firstly, anti-carbohydrate antibody RAV-12 is a chimeric mouse-human IgG1 that shows in vitro and in vivo efficacy against human colon cancer cells (Loo et al., 2007). Secondly, anti-carbohydrate antibody HMMC-1 has shown in vitro efficacy against human ovarian cancer. HMMC-I is a fully human antibody generated by transchromosomal KM mice (Nozawa et al., 2004).
International patent application No. WO 2005/108430 discloses an anti-cancer mouse monoclonal antibody which is designated SC104. The CDR sequences of this antibody are set out in Table 1. The disclosure of this application is incorporated herein by reference. The exact nature of antigen to which SC104 binds is unclear but WO2005/108430 suggests that the antigen is a sialyltetraosyl carbohydrate. It is also disclosed that SC104 is capable of directly inducing cell death without the need for immune effector cells. As described in co-pending international patent application No. WO 2010/105290 a number of humanised versions of SC104 have been developed. The disclosure of this application is also incorporated herein by reference.
The therapeutic treatment of human cancers is challenging and can, in some cases, be enhanced by correlating molecular biomarkers with treatment outcome. For example mutations in the genes KRAS (alternatively named ki-ras or k-ras) or BRAF give rise to proteins with altered signalling properties in the tumour cells. Mutations in these biomarkers are known to correlate with unsuccessful outcomes in cancer treatment that use therapeutic antibodies targeting the epidermal growth factor receptor, for example cetuximab or panitumumab (Amado, Wolf et al. 2008; Karapetis, Khambata-Ford et al. 2008; Di Nicolantonio, Martini et al. 2008; Loupakis, Ruzzo et al. 2009; Lievre, Bachet et al. 2006). The KRAS mutations are of particular medical significance as they occur in 35%-45% of colorectal cancer patients; BRAF mutations occur in less than 15% (Siena, Sartore-Bianchi et al. 2009). Furthermore, KRAS mutations are found in 70%-95% of pancreatic carcinoma tissues (Saif et al. 2007).